Colorectal cancer in humans is a leading cause of cancer death in the U.S.A. Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disorder characterized by hundreds to thousands of benign polyps in the colon, which if left untreated may become malignant. The mutant adenomatous polyposis coli (ApcMin/+) mouse is an effective model to study the initiation, growth, and progression of colorectal cancer. Genetic background greatly influences polyp number, size, position and stage in ApcMin/+ mice, and modifier genes can alter these phenotypes. The major goal of this proposal is to identify the gene or genes responsible for the novel Modifier of Min 4 (Mom4) phenotype on mouse Chromosome 2. Our preliminary studies have provided three lines of evidence for this novel locus: 1) a QTL analysis, 2) B6.C3H and C3H.B6 reciprocal congenic crosses, and 3) a BXH Rl line backcross. In Specific Aim 1, classical genetic crosses involving congenic and consomic mice will be used to narrow the boundaries of the Mom4 locus. In Specific Aim 2, we will prioritize candidate genes for investigation based on predetermined and experimental criteria. In Specific Aim 3, we will generate a transgenic mouse model to test the effects of the Mom4 gene. This project will lead to an understanding of how allelic differences can alter the tumor phenotype. The study of modifier genes will impact the prevention, diagnosis, and treatment of human colorectal cancer. PUBLIC HEALTH RELEVANCE: Colorectal cancer in humans is a leading cause of cancer death in the U.S.A. The project will find genes that are associated with the risk of developing cancer. This information can be used to develop and new preventative and treatment options for colorectal cancer.